In the field of biodegradable polymers for biomedical applications, such as biodegradable medical devices or the time controlled release of drugs, one of the biggest challenges is related to controlling the polymer properties for a given application. Crystallinity, solubility, molecular weight (MW), molecular weight distribution (MWD) and chemical structure of repeat units of polymers play important roles in such controlling the required properties. To meet specific requirements of the designed application, two or more different monomers, e.g. glycolide and lactide, are randomly co-polymerized to produce random copolymers in various ratios to produce the required properties. However, the polymer chain of such a copolymer is heterogeneous because the polymer chains are randomly assembled. The repeatability and reproducibility of the release profile of drug system with such a copolymer are affected by the random nature of the polymerization reaction and the resulting random polymers.
Polyglycolic acid and polylactic acid are generally prepared from the cyclic diester of glycolic acid (glycolide) and lactic acid (lactide), respectively by ring opening addition polymerization in the presence of a catalyst, e.g., stannous octoate. In order to obtain copolymers, an often utilized route is the copolymerization with ring opening of the glycolide and lactides (L and D-Iactides) in the presence of tin 2-ethyl hexanoate.
Poly(lactide-co-glycolide) polymers therefore produced are heterogeneous, i.e., they are made up of a random sequence of lactate and glycolate structural units and it is statistically improbable any two chains will be identical. Ordinarily, properties of such copolymers are based, in part, upon the concentration of lactide and glycolide present in the starting reaction mixture. In addition, the formation of the copolymer is complicated by the fact that the reactivity of glycolide and lactide are different.
Formation of polyglycolic acid has been also reported by reaction of haloacetic acid with amine in solution at room temperature (Subramanyam et al, Journal of Polymer Science: Polymer Chemistry Edition, 22:1131, 1984) or by melting the sodium salt of halide substituted acetic acid at temperature of 150˜185° C. (Epple et al, Macromol. Chem. Phys. 200:2221, 1999). Nevertheless, copolymers of haloacetic acid and haloproponic acid or poly(lactide-co-glycolide) have never been demonstrated with these methods, maybe because of the reactivity difference between the different monomers in these polymerization methods.
Gilding et al. have reported that pure polyglycolide is about 50% crystalline and pure poly-L-lactide is about 37% crystalline. (Polymer, 20:1459 (1979)). It has been also reported that poly(lactide-co-glycolide) polymers are amorphous between the compositional range of from 25 to 75 mole percent glycolide. This observation is explained by the amorphous character of the copolymer. To obtain crystallinity, extensive lengths of the chain need steric regularity which may be achieved with precise sequence control.
An attempt to provide a copolymer having a controlled sequence of alternating units of lactic acid and polyglycolic acid was described in U.S. Pat. No. 3,960,152 (the “152 patent”). According to the '152 patent, lactic acid and glycolic acid are formed into a cyclic diester (3methyl-1,4-dioxane-2,5-dione). When the cyclic diester is opened and added to a polymer chain, the lactic acid unit and glycolic acid unit are said to be adjacent in the polymer chain. However, there is no way to control the ring opening polymerization such that the ring opens at the same position every time. Thus, the ring opening and subsequent addition cannot be strictly uniform and the final product does not contain regularly alternating lactic acid units and glycolic acid units, i.e., the resulting polymer is not homogeneous. Moreover, the application of the method in the '152 patent is limited to those copolymers with two structural units only.
In U.S. Pat. No. 5,349,047 (the “047 patent”) Hermes and Huang described polyesters having predetermined monomeric sequence which are produced by stepwise addition of monomeric hydroxyacids to a growing polymeric chain. In the '047 patent, the bifunctional hydroxyacids monomers are protected with different protection methods for its hydroxyl group and carboxyl group respectively. By selective deprotection, the monomer units are free to be added into the growth polymer chain or to be added by another monomer unit. With such a protection/deprotection approach, polyesters can be produced in any designed sequences. However, the longest polymer chains demonstrated by stepwise addition have only 16 structural units with MW of 2081 g/mol which is not enough to be utilized in practical application.
Therefore, there is a need to explore other methodology for constructing polyesters having a predetermined sequence of structural units.